An oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule (the oxidant, also called the hydrogen donor or electron donor) to another (the reductant, also called the hydrogen acceptor or electron acceptor). Oxidoreductases are classified as EC 1 in the EC number classification of enzymes. Oxidoreductases can be further classified into 22 subclasses. Many oxidoreductase enzymes are metalloenzymes that contain one or more metal ions. Some exemplary enzymes in this group are 1-deoxy-d-xylulose-5-phosphate reductoisomerase, 5-lipoxygenase, 17-alpha hydroxylase, alcohol dehydrogenase, aldosterone synthase, aromatase, cyclooxygenase, heme oxygenase, indoleamine 2,3-dioxygenase, lanosterol demethylase, nitric oxide synthase, retinoic acid hydroxylase, vascular adhesion protein-1, and xanthine oxidase.
Despite the importance of the metal ions to metallo-oxidoreductases activity, the current evaluation and development of metallo-oxidoreductases inhibitors typically ignores the activity of the metal ions in the design of the inhibitors. For example, a survey of decades of research on xanthine oxidase (XO) inhibitors reveals many of the studies were randomly performed, that it was difficult to rationalize a division of the different type of inhibitors, and none of the research focused on inhibitors that would interact with the metal ions of XO. See Borges et al., Current Medicinal Chemistry, 9:195-217 (2002), herein expressly incorporated by reference.
As described in more detail herein, certain candidate metallo-oxidoreductase inhibitors are known in the art. While some of these candidates have shown promise, there is a need for novel selective inhibitors of oxidoreductase enzymes, such as 5-lipoxygenase, 17-alpha hydroxylase, alcohol dehydrogenase, aldosterone synthase, aromatase, cyclooxygenase, heme oxygenase, indoleamine 2,3-dioxygenase, lanosterol demethylase, nitric oxide synthase, retinoic acid hydroxylase, vascular adhesion protein-1, and xanthine oxidase. The presently disclosed subject matter addresses, in whole or in part, these and other needs in the art.